Project Summary/Abstract: Marked sleep disruption has long been recognized as a prevalent feature of Alzheimer's disease. However, a corpus of new data suggests that sleep abnormalities are not simply a symptom of aging and Alzheimer's disease, but an intimate and bi-directional component of their pathophysiology that further contributes to impairments in long-term memory consolidation. Despite these emerging links, the pathological role of tau protein aggregation in disrupting human NREM sleep physiology remains un-investigated, as does the potential consequence of such disruption for explaining impaired long-term memory consolidation in Alzheimer's disease. Moreover, the longitudinal inter-relationship between tau aggregation, NREM sleep physiology deterioration, and the impairment in hippocampal memory that typifies Alzheimer's disease, is also unknown. Addressing these questions, this proposal will test the hypothesis that early accumulation of tau in the human medial temporal lobe selectively impairs NREM sleep oscillations, thereby diminishing long-term memory consolidation and associated aspect of cognition, both cross-sectionally and longitudinally. Such findings may help identify a unique mechanistic pathway (sleep disruption) through which Alzheimer's disease pathology transacts memory impairment, and further define a new therapeutic target (sleep restoration) for intervention in aging and Alzheimer's disease. Additionally, such data would motivate a greater sensitivity of physicians to inquire about, diagnose and treat sleep difficulties across all ages. More generally, support for our hypothesis would argue for improved public health policies advocating for sufficient quality sleep throughout adulthood?a memorandum that may lower dementia risk and maintain cognitive health across the populous.